Effect of acidic environment on the response of endothelial cells to irradiation: Implications for microbeam radiation therapy

Kim, Eun‐Hee

doi:10.3109/09553002.2014.887867

Cited by 2 publications

(2 citation statements)

References 32 publications

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“…Consistent with our observations, it was reported in the rat aortic ring model that acidity induced a marked delay in microvascular growth [29]. Also, acidity delayed migration of endothelial cells in irradiated wounds [30]. …”

Section: Discussionsupporting

confidence: 92%

Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies

et al. 2016

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Anti-angiogenic treatments targeting the vascular endothelial growth factor or its receptors have shown clinical benefits. However, impact on long-term survival remains limited. Solid tumors display an acidic microenvironment that profoundly influences their biology. Consequences of acidity on endothelial cells and anti-angiogenic therapies remain poorly characterized and hence are the focus of this study. We found that exposing endothelial cells to acidic extracellular pH resulted in reduced cell proliferation and migration. Also, whereas VEGF increased endothelial cell proliferation and survival at pH 7.4, it had no effect at pH 6.4. Furthermore, in acidic conditions, stimulation of endothelial cells with VEGF did not result in activation of downstream signaling pathways such as AKT. At a molecular level, acidity significantly decreased the expression of VEGFR-2 by endothelial cells. Consequently, anti-angiogenic therapies that target VEGFR-2 such as sunitinib and sorafenib failed to block endothelial cell proliferation in acidic conditions. In vivo, neutralizing tumor acidity with sodium bicarbonate increased the percentage of endothelial cells expressing VEGFR-2 in tumor xenografts. Furthermore, combining sodium bicarbonate with sunitinib provided stronger anti-cancer activity than either treatment alone. Histological analysis showed that sunitinib had a stronger anti-angiogenic effect when combined with sodium bicarbonate. Overall, our results show that endothelial cells prosper independently of VEGF in acidic conditions partly as a consequence of decreased VEGFR-2 expression. They further suggest that strategies aiming to raise intratumoral pH can improve the efficacy of anti-VEGF treatments.

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Section: Discussionsupporting

confidence: 92%

Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies

et al. 2016

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“…This is probably a function of tumor vascularization (i.e., tumor cell specific release of VEGF/PDGF/ Dll4) [74], tumor microenvironment effects on endothelial characteristics (i.e., radiosensitivity, acidity) [75][76][77], and/or tumor vascular architecture [78][79][80]. In order to overcome this challenge, it will be important to investigate the potential use of 'maintenance' therapies further (i.e., to prevent any vascular rebound) following radiation exposure, and to optimize USMB therapy treatment parameters and the timing of any combination treatment regimens in order to ensure that tumor responses are as efficient as they can be.…”

Section: • Mechanisms Behind Mechanical Perturbation Of Cell Membranesmentioning

confidence: 99%

Biomechanical Effects of Microbubbles: From Radiosensitization to Cell Death

Kaffas

Czarnota

2015

Future Oncol.

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Ultrasound-stimulated microbubbles have been demonstrated to mechanically perturb cell membranes, resulting in the activation of biological signaling pathways that significantly enhance the effects of radiation. The underlying mechanism involves augmented ceramide production following both microbubble stimulation and irradiation, leading to rapid and extensive endothelial apoptosis and tumor cell death as a result of vascular collapse. Endothelial cells are particularly sensitive to ceramide-induced cell death due to an enriched presence of sphingomyelinase in their membranes. In tumors, this consequent rapid vascular shutdown translates to an overall increase in tumor responses to radiation treatments. This review summarizes the groundwork behind endothelial-based radiation enhancement with ultrasound-stimulated microbubbles, and presents ongoing research on the use of microbubbles as therapeutic agents in cancer therapy.

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Effect of acidic environment on the response of endothelial cells to irradiation: Implications for microbeam radiation therapy

Abstract: The microenvironmental acidity and the size of beam opening in MRT may greatly affect the repair of irradiated peak regions via migration of EC from unirradiated valley regions.

Cited by 2 publications

References 32 publications

Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies

Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies

Biomechanical Effects of Microbubbles: From Radiosensitization to Cell Death

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